A composition composed of ceftriaxone sodium and sulbactum sodium

ABSTRACT

The present invention provides a composition composed of ceftriaxone sodium and sulbactam sodium, a pharmaceutical composition comprising the same and the application thereof. The composition is characterized in that diffraction peaks at specific angles are included in the X-ray powder diffraction analysis spectrum. The pharmaceutical composition according to the present invention have better antibacterial activity and stability compared with known compositions, and are thus very suitable for the treatment of bacterial infections, especially for the treatment of refractory urogenital system infections caused by  Neisseria gonorrhoeae  which is drug-resistance to a variety of antibiotics (β-lactams, tetracyclines, macrolides, fluoroquinolones and aminoglycosides).

TECHNICAL FIELD

The present invention relates to a composition, and particularly relatesto a composition composed of ceftriaxone sodium and sulbactam sodium.The present invention also relates to a pharmaceutical compositioncomprising the composition and applications thereof.

BACKGROUND

Ceftriaxone is a third generation cephalosporin antibiotic and itssodium salt is commonly used in clinic. Ceftriaxone sodium has greatantibacterial activity against a variety of gram-negative bacteria andsome gram-positive bacteria (such as Escherichia coli, Klebsiellapneumoniae, Neisseria gonorrhoeae and the like) and can be used for thetreatment of infectious diseases caused by sensitive bacteria, but itsapplication has certain limit due to insensitivity toMethicillin-Resistant Staphylococcus aureus (MRSA) and Enterobactercloacae. Sulbactam is a β-lactamase inhibitor. In the prior art, someoneformulated sulbactam sodium and ceftriaxone sodium into a compoundformulation, which improves the antimicrobial spectrum and sensitivityto drug-resistant bacteria of ceftriaxone.

Stable quality of a drug is critical for ensuring the safety of druguse. The crystalline form (crystalline morphology) of crude drug plays avery important role on stabilizing the drug quality. Regarding thequality control of drug, different crystalline forms (crystallinemorphologies) may have different stability and thereby affect the drugquality. If the crystalline form (crystalline morphology) of a drug isfixed, the quality is more stable and easier to control; otherwise, itmay cause the quality differences between drug batches, making theirstability different from each other.

Prior research showedthat ceftriaxone sodium can show many differentcrystalline morphologies. It was reported in Chinese Journal ofAntibiotics (2007, 32(11): 672-678) that the single crystal structure ofceftriaxone sodium was simulated by means of a software, provide usefulreference for researchers on the crystal of ceftriaxone sodium. Threecrystalline form subtypes of ceftriaxone sodium were reported inPharmaceutical Journal (2014, 49(7): 1034-1038) which have differencesin all the following aspects: salt-forming rate, crystallinity,compatibility with butyl rubber closures and the like, thereby probablyaffecting the efficacy of drugs.

Sulbactam sodium is also a substance which may be present in differentcrystalline forms. It is reported in Biochemistry (1981, 20(13):3680-3687) that sulbactam sodium can be crystallized from the mixedsolvent of ethyl acetate and n-butanol, and its single crystal structureis also disclosed. It is reported in Huaihai Medicine (2005, 23(5): 423)that sulbactam sodium was prepared by using different solvents such asacetone, ethyl acetate, methanol, ethanol and the like, four differentkinds of crystal which varied significantly in morphology, density andflowability were obtained. A sulbactam crystal is disclosed inCN103113390A, the content of which can maintain stable within 24 months.

In order to obtain pharmaceutical compound formulations of ceftriaxonesodium and sulbactam sodium with better efficacy as compared with singleprescription preparations, it is necessarily required that thepharmaceutical compound formulations have stable quality. However, thecompound formulations show greater complexity in the respect ofpreparation, efficacy and the like, as compared with the singleprescription preparations. In the respect of crystalline form, sinceboth ceftriaxone sodium and sulbactam sodium have multiple differentcrystals in the prior art, which made the complexity of the crystallineform of compound drug, meanwhile, the process of composition preparationmay also have an unpredictable effect on the preparation of crystal.

Studies have found that the known compound preparation of ceftriaxonesodium and sulbactam sodium shows a situation where the crystalline formis not stable.

It is reported in CN102462684A that under a condition of low temperatureand inert gas, ceftriaxone sodium, sulbactam sodium and a lyoprotectantwere dissolved in 70% ethanol to form a solution; the solution was addedwith a pH adjusting agent and subjected to lyophilization to form aeutectic powder, in which the active ingredient substantially did notdegrade within 36 months. However, the eutectic powder comprised manycomponents such as ceftriaxone sodium, sulbactam sodium, alyoprotectant, a pH adjusting agent and the like after all, which mighthave certain effect on the crude drug itself. Studies have shown thatthe eutectic powder had a stable content, but it didn't form a stablecrystal which means that it was still unstable in the sense ofcrystallography.

Crystal is an orderly arrangement presented by substance particles on amicroscopic level, while the presence and the state of presence of thecrystal cannot be predicted effectively yet due to the limitations ofscientific and technological level nowadays. Inventors expect to improvethe quality of product, lengthen the shelf life, and improve the economyand safety of the compound formulation of ceftriaxone sodium andsulbactam sodium through in-depth research.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to provide a stablecomposition composed of ceftriaxone sodium and sulbactam sodium so as tosolve the existing problems in the prior art such as poor stability,poor efficacy, short shelf life and the like.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising a stable composition composed of ceftriaxonesodium and sulbactam sodium.

A further object of the present invention is to provide application ofsaid pharmaceutical composition in the preparation of antibacterialdrug.

When conducting studies on stability, the inventors found that, after 30months of storage, the compound formulation of ceftriaxone sodium andsulbactam sodium would show slightly turbid after dissolved in water.When the preparation process of the compound formulation was furtherrepeated, it was found that the crystalline form of the products hadsome problems: although the raw materials ceftriaxone sodium andsulbactam sodium used had certain crystalline forms, the compoundformulation prepared was amorphous. The instability of the crystallineform may be one of the reasons leading to the occurrence turbidity ofcompound formulation after long time storage.

When improving the preparation process of the compound formulation, theinventors surprisingly obtained a composition of ceftriaxone sodium andsulbactam sodium having specific crystal morphology.

One technical solution according to the present invention is:

a composition composed of ceftriaxone sodium andsulbactam sodium, in theX-ray powder diffraction analysis spectrum of which, the following peaksat 2θ±0.2° angles are included: 11.2, 14.3, 17.8, 19.3, 21.2, 22.8 and23.8.

Preferably, in the X-ray powder diffraction analysis spectrum of thecomposition according to the present invention, the following peaks at2θ±0.2° angels are further included:12.6, 16.7, 18.4, 20.0, 20.4 and28.0.

Another technical solution according to the present invention is: acomposition composed of ceftriaxone sodium and sulbactam sodium, in theX-ray powder diffraction analysis spectrum of which, the followinginterplanar crystal spacings ±0.2 Å are included:7.9, 6.2, 5.0, 4.6,4.2, 3.9 and 3.7.

Preferably, in the X-ray powder diffraction analysis spectrum of thecomposition according to the present invention, the followinginterplanar crystal spacings ±0.2 Å are further included: 7.1, 5.3, 4.8,4.4, 4.3 and 3.2.

The composition according to the present invention is a crystallinesubstance (crystal). X-ray powder diffraction analysis is anauthoritative means for identifying crystals in the art; in the spectrumobtained by X-ray powder diffraction analysis, generally speaking, thecharacteristics of the crystal may be better reflected by peaks at thelow 2θ angle, high interplanar crystal spacing, having a clear andcomplete morphology and higher intensityand. Additionally, due toproblems such as the preferred orientation of the sample, a singleparameter such as peak height of the characteristic peak, peak area andthe like is often not characteristic and may not be used alone tocharacterize the crystal. In accordance with the general principles ofcrystallography, the inventors selected a series of characteristic 2θangles and interplanar crystal spacings which can scientificallycharacterize the composition according to the present invention.

In the infrared absorption spectrum analysis, the composition accordingto the present invention have absorption peaks at the following wavenumbers ±5 cm⁻¹: 3255, 1742, 1604, 1539, 1398, 1302, 1198, 1124, 1032,897, 804, 600 and 479.

Preferably, in the infrared absorption spectrum analysis, thecomposition according to the present invention further has an absorptionpeak at the following wave numbers ±5 cm⁻¹: 3441, 3116, 2938, 1500 and1099.

In the differential scanning calorimetry analysis, the compositionaccording to the present invention shows an exothermic peak at269.6±0.5° C.

With respect to the characterization of crystals, the accuracy of theinfrared absorption spectroscopy and the differential scanningcalorimetry analysis may be inferior to that of the X-ray powderdiffraction analysis, but they are two common means for identifyingsubstances and thus may give reference to the characterization of thecomposition according to the present invention.

The composition according to the present invention may be prepared bythe following method: raw materials ceftriaxone sodium and sulbactamsodium are taken and ground until the particle size is 25 μm-88 μm, andmixed well.

Preferably, the particle size is 25 μm-47 μm, 38 μm-62 μm or 58 μm-88μm.

Preferably, in the present invention, the grinding may be that theceftriaxone sodium raw material and the sulbactam sodium raw materialare firstly ground respectively and then ground together; and thegrinding may also be that the ceftriaxone sodium raw material and thesulbactam sodium raw material are ground together directly.

Preferably, in the present invention, the particle size refers to themedian diameter D₅₀.

Preferably, in the present invention, the grinding is performed by aball mill.

Preferably, in the present invention, the mixing is performed by asingle-cone ribbon mixer.

More preferably, the rotational speed of the single-cone ribbon mixer is25˜40 rpm, and the mixing time is between 10˜25 minutes.

When preparing the composition according to the present invention, theinventors use a grinding method. During grinding, the physical forceprompts the sufficient contact between ceftriaxone sodium and sulbactamsodium, and directly or indirectly affects the microscopic spatialstructure of a substance. The inventors have found that a specificdegree of grinding is very important for the product; in some cases theobtained products have low crystallinity; and the control of the degreeof grinding could be achieved to a certain extent by specifying theparticle size of the product after grinding. For example, screens withdifferent mesh numbers may be used during grinding, and screens withspecific mesh numbers may also be used to sieve the product aftergrinding. The particle size of the product may be determined byconventional methods in the art.

Although a preparation method of the composition according to thepresent invention is illustrated by way of example, it is not ruled outthat there are other methods by which the composition according to thepresent invention can be obtained.

Additionally, in order to simplify the drug production process to makethe subsequent preparation of pharmaceutical compositions moreconveniently, the two components of the composition according to thepresent invention may also be maintained at a certain ratio in advance.

Preferably, in the composition according to the present invention, theratio (in mass ratio) of ceftriaxone sodium (calculated by ceftriaxone)to sulbactam sodium (calculated by sulbactam) may be 1:1 to 8:1. In someexamples according to the present invention, the ratio is preferably1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1.

More preferably, in the composition according to the present invention,the ratio of ceftriaxone sodium (calculated by ceftriaxone) to sulbactamsodium (calculated by sulbactam) is 1:1 to 4:1.

Although some ratios of the components are listed, it is not ruled outother ratio by which the composition according to the present inventioncan be obtained.

With respect to the composition, technical features in theabove-mentioned preferred technical solutions may be combined freely andall combinations fall into the scope of the composition according to thepresent invention.

A further technical solution according to the present invention is:

a pharmaceutical composition comprising the composition according to thepresent invention.

Preferably, in the pharmaceutical composition according to the presentinvention, the composition according to the present invention is activeingredient.

Preferably, the pharmaceutical composition according to the presentinvention further comprises a pharmaceutical acceptable excipient.

Preferably, the pharmaceutical composition according to the presentinvention is powder for injection or injection solution, wherein morepreferably, the powder for injection is aseptic powder needle orlyophilized powder for injection.

Preferably, in the pharmaceutical formulation according to the presentinvention, the ratio (in mass ratio) of ceftriaxone sodium (based onceftriaxone) to sulbactam sodium (based on sulbactam) may be 1:1 to 8:1.In some examples according to the present invention, the ratio ispreferably 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1.

More preferably, in the pharmaceutical formulation according to thepresent invention, the mass ratio of ceftriaxone sodium (based onceftriaxone) to sulbactam sodium (based on sulbactam) is 1:1 to 4:1.

With respect to the pharmaceutical formulation, technical features inthe above-mentioned preferred technical solutions may be combined freelyand all combinations belong to the scope of the pharmaceuticalformulation according to the present invention.

Another further technical solution according to the present inventionis:

application of the composition or the pharmaceutical compositionaccording to the present invention in the preparation of antibacterialdrugs.

Preferably, in the present invention, the “antibacterial” according tothe present invention is anti-Neisseria gonorrhoeae, wherein morepreferably Neisseria gonorrhoeae having drug-resistance.

More preferably, in the present invention, the drug-resistance refers toresistance to β-lactams antibacterial drugs, tetracyclines antibacterialdrugs, macrolides antibacterial drugs, aminoglycosides antibacterialdrugs, and fluoroquinolones antibacterial drugs.

Definition: in the present invention,

The term “composition” refers to a combination formed by more than onesubstance.

The term “Pharmaceutical formulation” refers to a product preparedaccording to certain dosage form requirements, which complies withprovisions of relevant laws and regulations and meets requirements ofrelevant standards and may be directly provided to users for use,wherein, relevant laws and regulations include, but are not limited to,Drug Administration Law, Drug Registration and Management Regulation,Criterions for the Quality Control of Drug Manufacturing and the like;relevant standards include, but not limited to, Chinese Pharmacopoeia.

“aseptic powder needle”, “lyophilized powder for injection” or“injection solution”, into which excipient may be added or not added asneeded, and can be prepared by using conventional methods in the art.

“X-ray powder diffraction analysis”, “infrared absorption spectrumanalysis” and “differential scanning calorimetry analysis” areconventional analytical methods in the art. In addition, due todifferences in experimental conditions (including, but not limited to,particle size of samples, particle aspect ratio of samples, instrumenttypes, instrument accuracy, modes of operation, operators, etc.) and theinevitable experimental error (instrumental error, accidental error,etc.), it is impossible for the data in the present invention to becompletely absolute. In order to scientifically characterize thecomposition according to the present invention, the inventors specifythe error margin of the data depending on common knowledge in the art(for example, United States Pharmacopoeia USP35-NF30 describes that inthe X-ray powder diffraction analysis, the instrumental error may reach0.2°) and the situation of the composition according to the presentinvention. However, it will be understood that it is impossible forerror margin to cover all of the situations. It will also be understoodfor a person skilled in the art that the numerical value may fluctuatewithin the common range in the art, which all belong to the scope of thetechnical solutions of the present invention.

The “peak” in “characteristic peak”, “absorption peak” or “exothermicpeak” refers to a peak shows greater intensity than that of noise in thespectrum obtained by relevent analytical methods.

“Drug-resistant” or “drug-resistance” means that a microorganismdevelops resistance to a drug, so that the activity of the drug againstthe microorganism is reduced significantly.

A novel composition of ceftriaxone sodium and sulbactam sodium isobtained in the present invention through studies, and the compositionand pharmaceutical composition prepared from the same have betterantibacterial activity and superior stability (physical stability,chemical stability and bioactivity stability).

In particular, after 30 months of storage, the aqueous solutions of thecomposition and the formulation thereof according to the presentinvention have good clarity, the content of each of various impuritiesis less than 0.5%, and the crystallinity is essentially unchanged,exhibiting excellent physical and chemical stability. Furthermore,surprisingly, the composition and the pharmaceutical compositionaccording to the present invention have improved antibacterial activity,especially exhibit better antibacterial effect against a variety ofdrug-resistant Neisseria gonorrhoeae, and have unchanged activity after30 months of storage, showing superior bioactivity stability.

Due to excellent stability and bioactivity, the composition and theformulation thereof according to the present invention are quitesuitable for the treatment of bacterial infections, especially suitablefor the treatment of urogenital system infections caused by a variety ofrefractory and drug-resistant Neisseria gonorrhoeae.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction analysis spectrum forLyophilized Powder for Injection A in Comparative Example 1.

FIG. 2 shows the X-ray powder diffraction analysis spectrum for mixedpowder in Comparative Example 2.

FIG. 3 shows the X-ray powder diffraction analysis spectrum forComposition I in Example 1.

FIG. 4 shows the infrared absorption analysis spectrum for Composition Iin Example 1.

FIG. 5 shows the X-ray powder diffraction analysis spectrum forComposition II in Example 2.

FIG. 6 shows the infrared absorption analysis spectrum for CompositionII in Example 2.

FIG. 7 shows the X-ray powder diffraction analysis spectrum forComposition III in Example 3.

FIG. 8 shows the infrared absorption analysis spectrum for CompositionIII in Example 3.

EMBODIMENT

Hereinafter, Comparative Examples, Examples and Test Examples are usedto further explain the present invention, but are not intended to limitthe technical solutions and the technical effects of the presentinvention.

Description: in the following Comparative Examples, Examples and TestExamples:

(1) The amount of ceftriaxone sodium/ceftriaxone sodium crystals iscalculated by ceftriaxone; the amount of sulbactam sodium/sulbactamsodium crystals is calculated by sulbactam, for example, “take 500 gceftriaxone sodium” means that the amount of ceftriaxone in the takenceftriaxone sodium is 500 g.

(2) The crystal morphology is measured by X-ray powder diffractionmethod using BRUKER D8 ADVANCE X-ray powder diffraction instrument underthe following measurement conditions: CuKa radiation, tube voltage 40kV, scanning range 5°-60°, scanning speed 17.7 s/step, step-length0.02°.

(3) In the infrared absorption spectrum analysis, the samples arepressed into tablets with KBr and then measured;

(4) STA409 integrated thermal analyzer is from a Germany company NETZSCHand is used in the differential scanning calorimetry method to performmeasurement. Measurement conditions: heating rate 10 K/min, flow rate ofprotective gas N₂ 30 mL/min, flow rate of purging gas N₂ 20 mL/min,temperature range 35-300□.

(5) The crystallinity is measured using the US Pharmacopoeia USP35-NF30method.

(6) The content of impurity is measured using HPLC method according tothe European Pharmacopoeia EP8.0 method.

(7) The clarity of solutions is measured according to the method ofChinese Pharmacopoeia 2015.

Comparative Example 1

According to the method described in Example 1 of CN102462684A, in asterile, dark condition and under nitrogen stream, 100 g of ceftriaxonesodium, 50 g of sulbactam sodium and 25 g of mannitol were added into 90ml of pretreated 70% ethanol solution which was cooled to below 10□which was placed in a non-metallic container, then dissolved completelywith stirring; the obtained solution was adjusted to a pH of 6.5 with0.1 mol/L aqueous solution of sodium bicarbonate, sterile filtration,subpackaged, placed in a lyophilizer filled with inert gas forpre-freeze (−48-−20□), and then subjected to pressure reduction,sublimation and drying to give the lyophilized powder named LyophilizedPowder for Injection A. Sampled and determined for crystal morphology,and the X-ray powder diffraction spectrum was showed in FIG. 1.

Comparative Example 2

Ceftriaxone sodium was prepared according to the following methoddescribed in Example 1 of CN102993215A, comprising: condensing 7-ACT andAE-active ester to give crude product of ceftriaxone sodium; taking 5 gof the crude product and dissolving them by adding 40 ml of water;adding 4.1 g of sodium iso-octoate into the obtained solution at 13° C.,stirring until the solution was clear, adjusting the solution to a pH of7.0 with 10% diluted hydrochloric acid, stirring for additional 30minutes to give a mother liquor; adding anhydrous ethanol slowly intothe mother liquor under stirring and stopping the stirring and theaddition when turbidity occurred; after standing for 25 minutes, slowlyadding anhydrous ethanol into the solution until a large amount ofcrystals were formed, all together 150 ml of anhydrous ethanol was used;filtering the resulting crystals, washing the cake to neutral with amixed solvent of anhydrous ethanol:water=4:1, washing with anhydrousethanol again and drying at 35□ under ambient pressure.

Sulbactam sodium was prepared according to the following methoddescribed in Example 1 of CN103113390A, comprising: taking the crudesulbactam sodium, and adding it into a mixed solvent ofN,N-dimethylformamide and water (3:1) the amount of which was 5 times(ml/g) of that of the crude sulbactam sodium, heating to 70□; stirringuntil the crude sulbactam sodium was completely dissolved, keeping thetemperature, adjusting the solution to a pH of 5.5, and making thesolution flow at a speed of 5 m/s through a direct current magneticfield of 0.5 T, the direction of which was perpendicular to the flowdirection of the solution, after magnetic treatment, adding activatedcarbon into the solution to decoloration, the amount of which was 0.3times (ml/g) of the mixed solvent, stirring 30 minutes and filtering togive a clear solution; adding ethanol into the clear solution and theamount of which is 5 times (ml/ml)of that of the mixed solvent,filtering to give the cake; washing the cake with distilled water 3times, and then drying 4 hours under reduced pressure to give sulbactamsodium.

Taking 1,000 g of ceftriaxone sodium and 500 g of sulbactam sodiumprepared according to the above-mentioned method, mixed well by a troughmixer under sterile condition to give mixed powder, which was sampledand subjected to crystal morphology measurement. The X-ray powderdiffraction spectrum was showed in FIG. 2. The mixed powder wassubpackaged under a sterile condition to give a sterile powder forinjection, named sterile powder for injection A.

Comparative Example 3

Taking saled 2,000 g of ceftriaxone sodium and 1,000 g of sulbactamsodium, mixed well through a trough mixer under sterile condition togive mixed powder, which was sampled and measured for crystalmorphology. The X-ray powder diffraction spectrum of the powder wassimilar to that of FIG. 2. The mixed powder was subpackaged under asterile condition to give a sterile powder for injection, named sterilepowder for injection B.

Example 1

1200 g of ceftriaxone sodium and 600 g of sulbactam sodium both preparedaccording to the method in Comparative Example 2 were taken and grindingtogether by a ball mill until the particle size D₅₀ was 25 μm-47 μm, andthen placed in a single-cone ribbon mixer (HF1600 type) and mixed well,with rotating speed of 30 rpm and mixing time was 25 minutes. After theoperation was completed, the material was taken out and a crystallinesubstance named Composition I was obtained.

The Composition I was sampled and measured for crystal morphology. TheX-ray powder diffraction spectrum was showed in FIG. 3. Main data of thespectrum were listed in Table 1.

Its infrared absorption was measured by infrared absorption spectrumanalysis. The spectrum was showed in FIG. 4. The main data of infraredabsorption peaks were listed in Table 2.

The Composition I was analyzed by the differential scanning calorimetry,and it was found that there was an exothermic peak at 269.51□.

TABLE 1 Main Data of X-ray Powder Diffraction Spectrum for Composition IInterplanar 2θ Crystal Peak Peak No. Angle (°) Spacing(Å) Height Aera 111.138 7.9372 1502 16530 2 12.521 7.0634 437 4363 3 14.289 6.1934 1101468918 4 16.638 5.3238 1798 12883 5 17.835 4.9692 1569 11493 6 18.4324.8096 883 7497 7 19.276 4.6008 2908 21910 8 19.978 4.4406 1034 12897 920.453 4.3386 1342 20418 10 21.171 4.1930 1651 17080 11 22.736 3.90791889 25822 12 23.769 3.7403 1299 15065 13 27.985 3.1856 2612 25393

TABLE 2 Main Data of Infrared Absorption Spectrum for Composition I No.Wave Number(cm⁻¹) 1 3441 2 3254 3 3117 4 2937 5 1742 6 1605 7 1539 81501 9 1398 10 1302 11 1198 12 1124 13 1099 14 1032 15 897 16 804 17 60018 480

Example 2

Taking saled ceftriaxone sodium 500 g and sulbactam sodium 500 g, andgrinding together by a ball mill until the particle size D₅₀ was 38μm-62 μm, then placed in a single-cone ribbon mixer (HF1600 type) andmixed well, with rotating speed of 40 rpm and mixing time was 20minutes. After the operation was completed, the material was taken outand a crystalline substance named Composition II was obtained.

The Composition II was sampled and measured for crystal morphology. TheX-ray powder diffraction spectrum was showed in FIG. 5. Main data of thespectrum were listed in Table 3.

Its infrared absorption was measured by infrared absorption spectrumanalysis. The spectrum was showed in FIG. 6. The main data of infraredabsorption peaks were listed in Table 4.

The Composition II was analyzed by differential scanning calorimetryanalysis, and it was found that there was an exothermic peak at 269.67°C.

TABLE 3 Main Data of X-ray Powder Diffraction for Composition IIInterplanar 2θ Crystal Peak Peak No. Angle(°) Spacing(Å) Height Aera 111.120 7.9500 1250 15628 2 12.521 7.0635 413 3990 3 14.272 6.2007 840951004 4 16.656 5.3181 1282 10862 5 17.815 4.9746 1514 10864 6 18.4314.8097 733 6124 7 19.292 4.5970 2475 16754 8 19.923 4.4528 537 18373 920.453 4.3386 1604 15208 10 21.171 4.1931 1308 13632 11 22.735 3.90801626 23393 12 23.825 3.7317 947 14460 13 27.966 3.1878 2090 21313

TABLE 4 Main Data of Infrared Absorption Spectrum for Composition II No.Wave Number(cm⁻¹) 1 3441 2 3254 3 3115 4 2939 5 1742 6 1605 7 1539 81499 9 1398 10 1302 11 1198 12 1124 13 1099 14 1032 15 897 16 804 17 60018 478

Example 3

930 g of commercially available ceftriaxone sodium was taken and ground;310 g of commercially available sulbactam sodium was taken and ground;and then these two raw materials were ground together by a ball milluntil the particle size D₅₀ was 58 μm-88 μm. The obtained powder wasplaced in a single-cone ribbon mixer (HF1600 type) and mixed well, withrotating speed of 25 rpm and mixing time of 10 minutes. After theoperation was completed, the material was taken out and a crystallinesubstance named Composition III was obtained.

The Composition III was sampled and measured for crystal morphology .The X-ray powder diffraction spectrum was showed in FIG. 7. Main data ofthe spectrum were listed in Table 5.

Its infrared absorption was measured by infrared absorption spectrumanalysis. The spectrum was showed in FIG. 8. The main data of infraredabsorption peaks were listed in Table 6.

The Composition III was analyzed by differential scanning calorimetry,and it was found that there was an exothermic peak at 269.69° C.

TABLE 5 Main Data of X-ray Powder Diffraction for Composition III 2θinterplanar crystal Peak Peak No. Angle(°) spacing(Å) Height Aera 111.159 7.9227 1519 16847 2 12.576 7.0326 458 4586 3 14.294 6.1913 1313270185 4 16.658 5.3176 1786 11679 5 17.851 4.9647 1873 10087 6 18.4504.8049 910 7192 7 19.315 4.5917 3940 24924 8 19.998 4.4362 859 11627 920.476 4.3338 1901 13788 10 21.208 4.1858 1446 16328 11 22.701 3.91381468 21912 12 23.807 3.7345 1261 15779 13 27.973 3.1870 1935 23623

TABLE 6 Main Data of Infrared Absorption Spectrum for Composition IIINo. Wave Number(cm⁻¹) 1 3441 2 3256 3 3117 4 2937 5 1742 6 1603 7 1539 81499 9 1398 10 1302 11 1198 12 1124 13 1099 14 1032 15 897 16 804 17 60018 480

Examples 4-8

800 g of ceftriaxone sodium and 200 g of sulbactam sodium; 1,150 g ofceftriaxone sodium and 230 g of sulbactam sodium; 2,700 g of ceftriaxonesodium and 450 g of sulbactam sodium; 1,330 g of ceftriaxone sodium and190 g of sulbactam sodium; 2,200 g of ceftriaxone sodium and 275 g ofsulbactam sodium, all of which were available in the market, were takenrespectively and then processed respectively according to the method inExample 2 to get Composition IV-Composition VIII respectively. It wasfound that the spectra of these five compositions were basically thesame as the spectra obtained in Examples 1-3 through X-ray diffractionanalysis.

Example 9

500 g of ceftriaxone sodium and 500 g of sulbactam sodium both availablein the market were taken and ground together by a ball mill until theparticle size D₅₀ was 104 μm-175 μm. Remaining operations of mixingmaterials were the same as Example 2. After the operations werecompleted, the material was taken out and subpackaged under sterilecondition to give Sterile Powder for Injection C.

500 g of ceftriaxone sodium and 500 g of sulbactam sodium both availablein the market were taken again and ground together by a ball mill untilthe particle size D₅₀ was below 10 μm. Remaining operations of mixingmaterials were the same as Example 2. After the operations werecompleted, the material was taken out and subpackaged under a sterilecondition to give Sterile Powder for Injection D.

Example 10

The compositions of Examples 1-8 were taken respectively, andsubpackaged under sterile condition to give Sterile Powder for InjectionI-Sterile Powder for Injection VIII.

The compositions of Examples 1-8 were taken respectively and processedaccording to the conventional process of lyophilized agents to giveLyophilized Powder for Injection I-Lyophilized Powder for InjectionVIII.

The compositions of Examples 1-8 were taken respectively and dissolvedwith 50 times amount of 0.9% sodium chloride aqueous solution andsubpackaged to give Injections I-VIII.

Test Example 1: Stability Test

Stability test was performed for composition I-Composition VIII, SterilePowder for Injection I, Sterile Powder for Injection II, Sterile Powderfor Injection IV, Lyophilized Powder for Injection I, Lyophilized Powderfor Injection II, Sterile Powder for Injection A , Sterile Powder forInjection B, Sterile Powder for Injection C, Sterile Powder forInjection D and Lyophilized Powder for Injection A obtained in theabove-mentioned Comparative Examples or Examples.

Test environment: 30 months of placement in an environment in which thetemperature was 25° C.±2° C. and the relative humidity was 60%±10%.

Test results: clarity of solution; content of impurities 1, 2, 3 and 4(wherein, impurities 1, 2 and 3 were respectively impurities A, B and Eof ceftriaxone sodium described in EP8.0, and impurity 4 was impurity Aof sulbactam sodium described in EP8.0), crystallinity and the like weremeasured and main test results were shown in Tables 7- 10.

TABLE 7 Situations of Various Samples at 0^(th) Month in Stability TestCon- Con- Con- Con- tent tent tent tent of of of of Impu - Impu - Impu -Impu - Clarity Crys- rity rity rity rity of tallinity 1 2 3 4 Solu-Samples (%) (%) (%) (%) (%) tion Composition I 90.5 0.12 0.08 0.09 0.11Clear Composition II 92.7 0.15 0.10 0.13 0.12 Clear Composition III 91.20.12 0.14 0.15 0.14 Clear Composition IV 92.1 0.11 0.20 0.12 0.10 ClearComposition V 90.4 0.18 0.27 0.19 0.10 Clear Composition VI 91.7 0.090.15 0.16 0.18 Clear Composition VII 92.5 0.21 0.10 0.15 0.13 ClearComposition 92.1 0.29 0.27 0.18 0.22 Clear VIII Sterile Powder 90.6 0.140.10 0.15 0.15 Clear for Injection I Sterile Powder 92.3 0.14 0.11 0.140.14 Clear for Injection II Sterile Powder 90.4 0.17 0.16 0.15 0.12Clear for Injection IV Lyophilized 87.6 0.12 0.20 0.16 0.17 Clear Powderfor Injection I Lyophilized 85.3 0.16 0.20 0.21 0.18 Clear Powder forInjection II Lyophilized / 0.32 0.14 0.22 0.11 Clear Powder forInjection A Sterile Powder / 0.18 0.13 0.26 0.18 Clear for Injection ASterile Powder / 0.33 0.19 0.18 0.19 Clear for Injection B SterilePowder 78.2 0.25 0.21 0.20 0.18 Clear for Injection C Sterile Powder72.1 0.22 0.31 0.23 0.16 Clear for Injection D

TABLE 8 Situations of Various Samples at 12^(th) Month in Stability TestCon- Con- Con- Con- tent tent tent tent of of of of Impu - Impu - Impu -Impu - Clarity Crys- rity rity rity rity of tallinity A B E G Solu-Samples (%) (%) (%) (%) (%) tion Composition I 90.4 0.14 0.10 0.11 0.14Clear Composition II 91.6 0.18 0.11 0.15 0.14 Clear Composition III 91.30.19 0.16 0.17 0.17 Clear Composition IV 92.0 0.21 0.25 0.17 0.14 ClearComposition V 89.2 0.16 0.30 0.24 0.13 Clear Composition VI 91.1 0.150.21 0.18 0.22 Clear Composition VII 92.4 0.26 0.24 0.21 0.14 ClearComposition 91.9 0.31 0.29 0.19 0.22 Clear VIII Sterile Powder 90.8 0.250.14 0.23 0.18 Clear for Injection I Sterile Powder 92.7 0.19 0.17 0.240.15 Clear for Injection II Sterile Powder 91.7 0.22 0.19 0.20 0.15Clear for Injection IV Lyophilized 85.8 0.16 0.23 0.19 0.18 Clear Powderfor Injection I Lyophilized 85.7 0.22 0.21 0.26 0.19 Clear Powder forInjection II Lyophilized / 0.53 0.38 0.46 0.54 Clear Powder forInjection A Sterile Powder / 0.69 0.52 0.32 0.41 Clear for Injection ASterile Powder / 0.53 0.48 0.37 0.43 Clear for Injection B SterilePowder 75.1 0.34 0.31 0.29 0.34 Clear for Injection C Sterile Powder73.2 0.29 0.42 0.33 0.30 Clear for Injection D

TABLE 9 Situations of Various Samples at 24^(th) Month in Stability TestCon- Con- Con- Con- tent tent tent tent of of of of Impu - Impu - Impu -Impu - Clarity Crys- rity rity rity rity of tallinity A B E G Solu-Samples (%) (%) (%) (%) (%) tion Composition I 89.2 0.18 0.21 0.17 0.25Clear Composition II 91.0 0.20 0.10 0.19 0.23 Clear Composition III 90.40.23 0.20 0.21 0.26 Clear Composition IV 91.7 0.21 0.29 0.23 0.17 ClearComposition V 88.2 0.28 0.33 0.29 0.30 Clear Composition VI 91.0 0.190.27 0.28 0.23 Clear Composition VII 91.6 0.33 0.27 0.32 0.22 ClearComposition 91.7 0.35 0.35 0.23 0.29 Clear VIII Sterile Powder 90.1 0.340.26 0.37 0.26 Clear for Injection I Sterile Powder 91.9 0.21 0.20 0.350.22 Clear for Injection II Sterile Powder 91.4 0.23 0.38 0.24 0.22Clear for Injection IV Lyophilized 85.2 0.23 0.29 0.33 0.22 Clear Powderfor Injection I Lyophilized 84.1 0.30 0.32 0.29 0.30 Clear Powder forInjection II Lyophilized / 0.83 0.77 0.88 0.62 Clear Powder forInjection A Sterile Powder / 0.99 0.82 0.79 0.70 Slightly for InjectionA turbid Sterile Powder / 0.78 0.97 0.85 0.75 Slightly for Injection Bturbid Sterile Powder 64.0 0.38 0.47 0.59 0.41 Clear for Injection CSterile Powder 62.2 0.39 0.56 0.44 0.33 Clear for Injection D

TABLE 10 Situations of Various Samples at 30^(th) Month in StabilityTest Con- Con- Con- Con- tent tent tent tent of of of of Impu - Impu -Impu - Impu - Clarity Crys- rity rity rity rity of tallinity A B E GSolu- Samples (%) (%) (%) (%) (%) tion Composition I 88.1 0.32 0.31 0.330.31 Clear Composition II 90.5 0.31 0.29 0.34 0.30 Clear Composition III88.2 0.38 0.37 0.28 0.34 Clear Composition IV 90.0 0.43 0.32 0.32 0.31Clear Composition V 87.1 0.37 0.45 0.32 0.33 Clear Composition VI 89.90.25 0.33 0.33 0.30 Clear Composition VII 90.5 0.38 0.41 0.39 0.33 ClearComposition 90.2 0.45 0.41 0.31 0.31 Clear VIII Sterile Powder 88.5 0.470.45 0.42 0.38 Clear for Injection I Sterile Powder 89.7 0.37 0.39 0.390.33 Clear for Injection II Sterile Powder 90.2 0.43 0.42 0.37 0.36Clear for Injection IV Lyophilized 84.9 0.39 0.39 0.43 0.38 Clear Powderfor Injection I Lyophilized 83.7 0.47 0.38 0.42 0.31 Clear Powder forInjection II Lyophilized / 1.23 1.05 1.12 0.78 Slightly Powder forturbid Injection A Sterile Powder / 1.36 1.12 0.94 1.19 Slightly forInjection A turbid Sterile Powder / 1.13 0.99 1.27 1.06 Slightly forInjection B turbid Sterile Powder 60.6 0.57 0.62 0.70 0.47 Clear forInjection C Sterile Powder 53.5 0.65 0.71 0.58 0.42 Clear for InjectionD

It can be seen from the results of the stability test that after 12months, the compositions and the formulations according to the presentinvention, as compared with Comparative Examples, had differences in thefollowing aspects such as crystallinity, impurities, clarity of solutionand the like, and after 30 months, such differences were moresignificant.

The formulations of Comparative Examples did not show a crystalline formand there was no data of crystallinity; however, the compositions andformulations according to the present invention had a crystallinity ofup to 90%, which kept substantially unchanged within 30 months, showingvery good physical stability.

At 24^(th)-30^(th) month, the formulations of Comparative Examplesshowed slight turbidity, and the compositions and the formulationsaccording to the present invention did not show turbidity.

Although, in the formulations of Comparative Examples, the contents offour impurities were equivalent to those in the compositions accordingto the present invention at 0^(th) month, the increase of impurities wasvery significant as time passed, and especially the contents of impurity1 (an isomer impurity of ceftriaxone) and impurity 4 (an open loopdegraded impurity of salbactam) ware greater than 1% and greater than0.5% respectively at 24^(th)-30^(th) month, fail to meet therequirements of EP 8.0; however, the increase of the four impurities inthe compositions and the formulations according to the present inventionwas not significant and fell into a defined scope, indicating very goodchemical stability. This finding revealed the possible presence of aclose relation between the generation of specific impurities and crystalmorphology.

Test Example 2: In Vivo Antibacterial Test

The stability test samples at 0^(th) month in test example 1 weresampled and subjected to in vivo antibacterial test; and the stabilitytest samples at 30^(th) month were sampled again, and subjected to invivo antibacterial test. Two in vivo antibacterial tests were bothperformed according to the following method.

2.1 Test Materials

Test Samples: Compositions I-VIII, Sterile Powder for Injection I,Sterile Powder for Injection II, Sterile Powder for Injection IV,Lyophilized Powder for Injection I, Lyophilized Powder for Injection II,Lyophilized Powder for Injection A, Sterile Powder for Injection A andSterile Powder for Injection B, all from the test example 1 at 0^(th)and 30^(th) month; and control drugs: ceftriaxone sodium, levofloxacinhydrochloride, azithromycin, doxycycline hydrochloride and spectinomycinhydrochloride, wherein, a batch of control drugs were bought at 0^(th)month of the stability test so as to match with the test samples at0^(th) month, and another batch of control drugs were bought at 30^(th)month of the stability test so as to match with the test samples at30^(th) month, and the time when the two batches were bought was withinone month from the date of their production.

Animals: ICR mice weighed 18-22 g, half male and half female.

Strains: ATCC700603 (Klebsiella pneumoniae), ATCC43069 (Neisseriagonorrhoeae), Q-R (quinolones-resistant Neisseria gonorrhoeae), T-R(tetracyclines-resistant Neisseria gonorrhoeae), PP-R(β-lactams-resistant Neisseria gonorrhoeae), MAC-R (macrolides-resistantNeisseria gonorrhoeae), SPE-R (spectinomycin-resistant Neisseriagonorrhoeae) and QS-R (ceftriaxone-resistant Neisseria gonorrhoeae),wherein, ATCC700603, and ATCC43069 were purchased from ATCC; QS-R wasprepared according to the method in a reference literature (ChinaTropical Medicine, 2010, 10 (8), 946-948); and other strains wereclinical isolates.

Protective agent: highly active dry yeast.

2.2 Test Method

Enhancing Cytotoxicity: the experimental strain was diluted to 10⁻² and10⁻³ with 5% highly active dry yeast after incubation of 18 hours; 0.5ml of the strain was injected intraperitoneally into mice to infectthem, obtaining a model of septicemia caused by the systemic infectionof the experimental mice; no protective measures was provided and thusmice died of infection; aseptic thoracotomy was performed timely on themice that died of infection, the heart blood or intracavity effusion wastaken and evenly coated on corresponding agar plates, and incubated for18 hours at 37° C.; and after identification, the strain was consistentwith the administrated infectious bacteria. The obtained strain was usedto infect mice again, and by performing this method 1-2 times, thecytotoxicity could be enhanced and was relatively stable.

Determining minimum lethal dose (MLD): the experimental strain wasdiluted with 5% highly active dry yeast to give diluted bacteriasolutions at different concentrations: 10⁻¹, 10⁻², 10⁻³ and 10⁻⁴, whichwere injected intraperitoneally into experimental animals (0.5 ml permouse) respectively to establish a model of septicemia. After infection,the number of dead mice was recorded. The minimum dose causing 100%death of mice was 1 MLD; as a dose in animal protection experiments, abacterial concentration which was one log lower than 1 MLD and theanimals infected by which all survived was named 0.1 MLD. Inexperiments, a bacteria concentration of 1 MLD was used as the positivecontrol for the infection experiments; and a bacteria concentration of0.1 MLD was used as the negative control for the infection. In bothpositive and negative control groups, only the bacteria wereadministrated and no antibiotic treatment was provided. The mortality ofthe positive group should be 70% or more, and the mortality of thenegative group should be 30% or less.

Pre-test for Determining the Dose Range of Test Samples: 1 MLD ofbacteria was formulated with 5% highly active dry yeast and used toinfect mice; immediately and after 6 hours, pre-tests were performedusing test samples at three different concentrations (highconcentration, medium concentration and low concentration), each dosegroup 4 mice; the survival number of mice after infection was recorded,and based on this result, the administration dose in the animalprotection test was designed. In the first exploration of theadministration dose, the fold differences in drug dose concentration ofeach group may be relatively great, and when the scope was determined,the fold differences may be reduced for another exploration until thesuitable drug dose concentration (that is, for the dose group withhighest concentration, 70% or more of infected animals survived, and forthe lowest dose group, no less than 70% of infected animals died) wasfound.

Animal Protection Test:

After drug dose concentrations at which 100% of mice died and drug doseconcentrations at which no death occurred were obtained in the pre-testsfor the test strains used to infect mice, mice that were fasted fromfood other than water for 18 hours before experiment, weighted 18-22 g;half male and half female, were randomly divided into the followinggroups: (1) ATCC700603 group, (2) ATCC43069 group, (3) Q-R group, (4)T-R group, (5) PP-R group, (6) MAC-R group, (7) SPE-R group and (8) QS-Rgroup; with five test sample concentrations each group, and 10 animalseach group. 10 animals were set as blank controls (equal volume ofsterile water for injection was administrated). Each mouse was injectedintraperitoneally with 0.5 ml of 1 MLD bacteria solution to establishinfection models; immediately and after 6 hours, test sample solutionsat different concentrations were injected subcutaneously respectively at0.2 ml per mouse; the mice were observed 7 consecutive days, and thedeath status of animals in each group were recorded. Autopsy andobservation with naked eye were performed on the dead mouse. The 50%effective dose (ED₅₀) and 95% confidence intervals were calculated byBliss method; t-test was performed and the significance of differencewas compared between groups. The lower the ED₅₀ was, the better theprotection for animals infected by bacteria the test sample provided.

2.3 Test Results

Main results of the animal protection tests were listed in Table 11 andTable 12, wherein, Table 11 showed the in vivo antibacterial ED₅₀ valuesof samples at 0^(th) month of the stability test, and Table 12 showedthe in vivo antibacterial ED₅₀ values of samples at 30^(th) month of thestability test.

TABLE 11 In Vivo Antibacterial ED₅₀ Values of Samples at 0^(th) Month ofthe Stability Test (mg/kg) Strains Test ATCC ATCC Q- PP- MAC- SPE- QSSamples 700603 43069 R T-R R R R -R Cef- 35 16 31 46 208 34 52 337triaxone Sodium Levo- — 25 573 48 37 36 67 72 floxacin Hydro- chlorideAzithro- — 24 43 62 49 487 59 63 mycin Doxy- — 37 55 456 52 58 52 105cycline Hydro- chloride Spectino- — 19 40 61 56 38 621 41 mycin Hydro-chloride Com- 21 11 24 34 47 27 42 62 position I Com- 23 13 21 37 50 2342 65 position II Com- 19 14 22 35 45 25 46 59 position III Com- 22 1520 32 44 26 47 62 position IV Com- 27 13 26 37 56 27 49 78 position VCom- 30 16 25 38 68 27 48 85 position VI Com- 31 17 25 38 60 29 52 82position VII Com- 28 15 27 39 66 28 50 84 position VIII Sterile 25 13 2432 42 25 46 64 Powder for Injection I Sterile 27 10 23 35 48 27 43 67Powder for Injection II Sterile 24 14 25 34 46 26 44 66 Powder forInjection IV Lyo- 27 14 22 35 43 24 46 62 philized Powder for InjectionI Lyo- 28 12 23 37 41 22 45 60 philized Powder for Injection II Lyo- 3116 27 39 62 26 50 95 philized Powder for Injection A Sterile 32 15 30 4056 29 48 92 Powder for Injection A Sterile 33 16 32 38 49 24 46 94Powder for Injection B Note: — represents Not Performed.

TABLE 12 In Vivo Antibacterial ED₅₀ Values of Samples at 30^(th) Monthof the Stability Test (mg/kg) Strains Test ATCC ATCC PP- MAC- SPE- QS-Samples 700603 43069 Q-R T-R R R R R Cef- 37 21 30 57 224 37 66 373triaxone Sodium Levo- — 30 564 43 42 41 72 82 floxacin Hydro- chlorideAzithro- — 31 40 59 55 497 65 69 mycin Doxy- — 32 51 432 47 62 51 99cycline Hydro- chloride Spectino- — 22 42 68 67 42 571 56 mycin Hydro-chloride Com- 23 16 22 42 50 29 52 71 position I Com- 25 15 20 46 53 2749 69 position II Com- 19 14 20 45 56 29 48 68 position III Com- 25 1724 42 51 25 57 70 position IV Com- 31 20 27 48 68 31 55 87 position VCom- 37 20 28 51 75 28 59 88 position VI Com- 38 22 28 47 65 33 57 92position VII Com- 36 23 26 49 71 31 59 94 position VIII Sterile 26 16 2141 51 28 48 75 Powder for Injection I Sterile 30 17 20 43 52 28 47 69Powder for Injection II Sterile 28 16 22 39 56 27 46 71 Powder forInjection IV Lyo- 30 18 26 42 53 25 47 70 philized Powder for InjectionI Lyo- 29 17 24 48 61 25 48 67 philized Powder for Injection II Lyo- 3526 41 78 93 53 79 153 philized Powder for Injection A Sterile 36 28 4775 102 48 87 174 Powder for Injection A Sterile 35 28 46 77 106 47 91188 Powder for Injection B Note: “—” represents Not Performed.

The test results showed that the compositions and the formulationsaccording to the present invention had better antibacterial activity,and especially exhibited significantly stronger inhibitory activityagainst various drug-resistant Neisseria gonorrhoeae bacteria and insome cases the activity may increase 3-4 times as compared withformulations in Comparative Examples.

In addition, the compositions and the formulations according to thepresent invention had relatively good stability of biological activity,and particularly the inhibition against various non-resistant andresistant Neisseria gonorrhoeae may always remain stable; and after 30months, the biological activity was basically unchanged. After 30months, the formulations in comparative example showed significantreduction of activity.

Although the present invention has been described above in detail withgeneral description, specific embodiments and tests, a person skilled inthe art may make suitable modifications or improvements thereon based onthe present invention. Thus, those modifications or improvements madewithout departing from the spirits of the present invention all belongto the content of the present invention. The background, summary of theinvention, and specific mode for carrying out the present invention areonly for illustrative purpose, but not used as evidence for identifyingthe prior art of the present invention.

1.-18. (canceled)
 19. A composition composed of ceftriaxone sodium andsulbactam sodium, wherein, in an X-ray powder diffraction analysisspectrum of the composition, the following peaks at 2θ±0.2° angles areincluded: 11.2, 14.3, 17.8, 19.3, 21.2, 22.8 and 23.8.
 20. Thecomposition according to claim 19, wherein, in the X-ray powderdiffraction analysis spectrum of the composition, the following peaks at2θ±0.2° angles are further included: 12.6, 16.7, 18.4, 20.0, 20.4 and28.0.
 21. The composition according to claim 19, wherein, in an X-raypowder diffraction analysis spectrum of the composition, the followinginterplanar crystal spacings ±0.2 Å are included: 7.9, 6.2, 5.0, 4.6,4.2, 3.9 and 3.7.
 22. The composition according to claim 21, wherein, inthe X-ray powder diffraction analysis spectrum of the composition, thefollowing interplanar crystal spacings ±0.2 Å are further included: 7.1,5.3, 4.8, 4.4, 4.3 and 3.2.
 23. The composition according to claim 19,wherein, in an infrared absorption spectrum, the composition hasabsorption peaks at the following wave numbers ±5 cm⁻¹: 3255, 1742,1604, 1539, 1398, 1302, 1198, 1124, 1032, 897, 804, 600 and
 479. 24. Thecomposition according to claim 21, wherein, in an infrared absorptionspectrum, the composition has absorption peaks at the following wavenumbers ±5 cm⁻¹: 3255, 1742, 1604, 1539, 1398, 1302, 1198, 1124, 1032,897, 804, 600 and
 479. 25. The composition according to claim 23,wherein, in the infrared absorption spectrum, the composition furtherhas absorption peaks at the following wave numbers ±5 cm⁻¹: 3441, 3116,2938, 1500 and
 1099. 26. The composition according to claim 19, wherein,in a differential scanning calorimetry analysis spectrum, thecomposition has an exothermic peak at 269.6±0.5° C.
 27. The compositionaccording to claim 19, wherein, the composition is prepared by a processcomprising the following steps of: taking ceftriaxone sodium rawmaterial and sulbactam sodium raw material, grinding until the medianparticle size D₅₀ is between 25 μm-88 μm, and mixing well to give thecomposition.
 28. The composition according to claim 26, wherein, themedian particle size D₅₀ is between 25 μm-47 μm, 38 μm-62 μm or 58 μm-88μm.
 29. A pharmaceutical formulation comprising the compositionaccording to claim
 19. 30. A pharmaceutical formulation comprising thecomposition according to claim
 27. 31. The pharmaceutical formulationaccording to claim 29, wherein, the pharmaceutical formulation is apowder for injection or an injection solution.
 32. The pharmaceuticalformulation according to claim 31, which is characterized in that thecomposition is a powder for aseptic powder needle for injection oflyophilized powder for injection.
 33. The pharmaceutical formulationaccording to claim 29, which is characterized in that, in thepharmaceutical composition, the mass ratio of ceftriaxone sodiumcalculated by ceftriaxone to sulbactam sodium calculated by sulbactam is1:1 to 8:1.
 34. The pharmaceutical formulation according to claim 33,which is characterized in that, the mass ratio is 1:1 to 4:1.
 35. Amethod for treatment of a bacterial infection disease which comprisesadministering a pharmaceutical formulation according to claim
 29. 36.Method according to claim 35, which is characterized in that, thebacteria infection is by the bacterium Neisseria gonorrhoeae havingdrug-resistance.
 37. The method according to claim 36, which ischaracterized in that, said drug-resistance refers to drug-resistance toa β-lactams antibacterial drug, a tetracyclines antibacterial drug, amacrolides antibacterial drug, a fluoroquinolones antibacterial drug oran aminoglycosides antibacterial drug.
 38. The method according to claim35, wherein, the bacterial infection disease is a urogenital systeminfection disease.